<p>Between October 2001 and May 2012 approximately 70% of U.S. military personnel killed in action and 75% wounded in action were the direct result of exposure to an explosion. As of 2008, it was estimated that close to 20% of all Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF) veterans had sustained some form of traumatic brain injury (TBI). Further, blast exposure is also a civilian problem due to the increased usage of explosives in terrorist attacks. Blast injury research has historically focused on the pulmonary system and the other air-containing organs which have been shown through extensive experimentation to be susceptible to blast overpressure injury. A shift in injury pattern during recent conflicts is characterized by decreased incidence of pulmonary injuries with an increase in TBI thought to be associated with blast exposure. This increase in observation of blast TBI has resulted in a large research effort to understand mechanisms and thresholds. However, due to the relatively sudden shift, much of this research is being conducted without a proper understanding and consideration of blast mechanics and interspecies scaling effects.</p><p>This dissertation used experimental and computational finite element (FE) analysis to investigate some large questions surrounding blast TBI research. An experimental investigation was conducted to determine the effects of modern thoracic body armor usage on blast pressure exposure seen by the body. To improve FE modeling capabilities, brain tissue mechanics in common blast TBI animal model species were investigated experimentally and computationally to determine viscoelastic constitutive behavior and measure interspecies variation. Meta-analysis of blast pulmonary literature was conducted to update interspecies scaling and injury risk models. To derive interspecies scaling and injury risk models for blast neurotrauma endpoints a meta-analysis of existing experimental data was used.</p><p>This dissertation makes major contributions to the field of injury biomechanics and blast injury research. Research presented in this dissertation showed that modern thoracic body armor has the ability to lower the risk of pulmonary injury from blast exposure by attenuating and altering blast overpressure. The study shows that the use of soft body armor results in the pulmonary injury threshold being similar to that for neurotrauma. The use of hard body armor results in the threshold for pulmonary injury occurring at higher levels than that of neurotrauma. This finding is important, as it helps to explain the recent shift in injury types observed and highlights the importance of continued widespread usage of body armor not only for ballistic protection but for protection from blast as well.</p><p>This dissertation also shows the importance of interspecies scaling for investigation of blast neurotrauma. This work looks at existing in vivo animal model data to derive appropriate scaling across a wide range of brain size. Appropriate scaling for apnea occurrence and fatality for blast isolated to the head was found to be approximately equal to a characteristic length scaling of brain size, assuming similar brain geometry. By combining the interspecies scaling developed and existing tests data, injury risk models were derived for short duration blast exposures.</p><p>The contributions and conclusions of this dissertation serve to inform the injury biomechanics field and to improve future research efforts. The consideration by researchers of the recommendations presented in this dissertation for in vivo animal model testing will serve to maximize the value gained from experimentation and improve our understanding of blast injury mechanisms and thresholds. The injury risk models presented in this work help to improve our ability to prevent, diagnose, and treat blast neurotrauma.</p> / Dissertation

abstract: Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for 70-90% of all TBI cases, yet its neuropathophysiology is still poorly understood. While a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (post-natal day 20) to repeat weight drop impact. Animals were anesthetized and subjected to sham or rmTBI once per day for 5 days. At 14 days post injury (PID), magnetic resonance imaging (MRI) revealed that rmTBI animals displayed marked cortical atrophy and ventriculomegaly. Specifically, the thickness of the cortex was reduced up to 46% beneath and the ventricles increased up to 970% beneath the impact zone. Immunostaining with the neuron specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker, 4-Aminophyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents. / Dissertation/Thesis / Masters Thesis Biology 2014

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Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with exposure to repetitive head impacts (RHI) in contact sports. No treatments are currently available. Much of the focus in CTE has been on the microtubule-binding protein tau, which tends to accumulate within neurons and glia around blood vessels at the depths of cortical sulci. The mechanisms of tau accumulation and propagation in CTE are still unknown. The predilection for the perivascular region suggests inherent structural and/or cellular vulnerabilities in this area. Astrocytes are glial cells in this perivascular region that help form the blood brain barrier (BBB) and the neurovascular unit (NVU). Their endfeet envelop blood vessels and help transport nutrients from the blood into the brain, as well as clear harmful waste products out of the brain. Astrocytes are also vital players in many of the brain’s other normal physiological functions, including providing structural and metabolic support to neurons and maintenance of ion and water homeostasis. In response to injury or disease, astrocytes undergo a series of structural and functional changes in a process known as reactive astrogliosis. Astrogliosis is widely considered a hallmark of brain pathology, however, only recently have we begun to understand its functional implications. Astrocytes can respond heterogeneously to CNS insults, including either loss or increase of homeostatic functions, or gain of new, possibly toxic functions. These different astrocytic responses can either assist in recovery or further exacerbate injury. Our current understanding of how astrocytes are altered in RHI and CTE is limited. A degenerative phenotype has been identified in older donors with later stage CTE, but its presence in younger donors with earlier stage disease is unknown. The hypothesis of this study is that exposure to repetitive head trauma causes astrocytes to become reactive and adopt altered phenotypes, including loss of homeostatic functions, in brain areas known to be biomechanically susceptible to the shearing forces of head trauma, such as the perivascular region and interface of the grey and white matter at the depth of the cortical sulcus. These altered phenotypes are expected to be found in athletes with and without pathological tau deposition, highlighting astrocytes as potential therapeutic targets in the post-traumatic injury cascade. Specifically, I seek to characterize reactive astrocyte phenotypes and assess changes in their perivascular function in the brains of former American football players with and without a neuropathological diagnosis of CTE.

Subconcussive impacts have become a growing concern particularly with respect to contact sports. It is believed that minimal head impacts can cause cerebral perturbations that initiate an immune response creating a window of vulnerability. Evidence suggests that additional head insults sustained during this window of vulnerability elicit an exaggerated inflammatory response and exacerbate cognitive deficits. Therefore, determining the lower limits of systematic perturbation resulting from low-level impacts is of critical importance in expanding our understanding of cerebral vulnerability and recovery. However, the vast majority of experimental investigations of subconcussion fail to model single impact events and instead focus on cumulative insults. Additionally, these animal models employ impact magnitudes used to model mild Traumatic Brain Injury. The present investigation aimed to address this gap in knowledge through the utilization of a pneumatically controlled, closed-head, blunt impact device capable of producing repeatable, defined, subconcussive head impacts within a rat model. Thermography was used as a noninvasive measure of inflammation and system perturbations with respect to local (head) and global (thorax and abdomen) temperature changes. Cognitive function was assessed using an Open Field Test and Novel Object Recognition test. Neuroinflammation was measured by assessment of GFAP and iba-1 within the hippocampus and corpus callosum. To investigate the tolerance and the persistence of cerebral vulnerability, measurement outcomes were assessed at six timepoints of recovery, 0, 0.5, 1, 4, 7, and 14 days. Thermal disturbances were detected directly after impact, followed by an apparent recovery, 0.5- and 1-day post-impact. A latent temperature increase was observed after 4- and 7-days of recovery coinciding with decreased risk-avoidance behaviors, a modest upregulation of iba-1, and a marked downregulation of GFAP. Short-term memory deficits became apparent after 7-days of recovery. A decrease in locomotor activity and an upregulation of GFAP was observed concomitant to a persistent decrease in risk-avoidance despite thermal, short-term memory, and iba-1 measurements recovery 14-days post-impact. Overall, these results indicate that low magnitude subconcussive impacts can produce latent thermal, behavioral, and histological disturbances uncharacteristic for a head injury model suggestive of a biomechanical threshold of altered pathodynamics that fail to fully recover after 14 days.

The focus of this dissertation was the biomechanics of blast-induced traumatic brain injury (bTBI). This study had three specific aims. One of the specific aims was to investigate the thoracic mechanism of bTBI by characterizing the cerebral blood pressure change during local blast exposure to head or chest in a rat model. This model utilized a shock tube to simulate the blast wave. The results showed that there is a blood pressure rise with high amplitude and short duration during both Head-Only and Chest-Only exposure conditions. It was shown that cerebral blood pressure rise was significantly higher in Chest-Only exposure, and resulted in astrocyte reactivation, and infiltration of blood-borne macrophages into the brain. It was concluded that due to chest exposure to a blast wave, high amplitude pressure waves that transfer from thoracic large vessels to cerebrovasculature can lead to blood-brain barrier disruption or perivascular injury and consequently trigger secondary neuronal damage. The second and third aims were related to the viscoelasticity and heterogeneity of brain tissue respectively for blast rate loading conditions. For the second specific aim, a novel test method was developed to apply shear deformation to samples of brain tissue with strain rates in the range of 300 to 1000 s-1. The results of shear tests on cylindrical samples of bovine brain showed that the instantaneous shear modulus (about 6 kPa) increased about 3 times compared to the values reported in the literature. For the third specific aim, local viscoelastic behavior of rat brain was characterized using a micro-indentation setup with the spatial resolution of 350 mm. The results of micro-indentation tests showed that the heterogeneity of brain tissue was more pronounced in long-term shear moduli. Moreover, the inner anatomical regions were generally more compliant than the outer regions and the gray matter generally exhibited a stiffer response than the white matter. The results of this study can enhance the prediction of brain injury in finite element models of TBI in general and models of bTBI in particular. These results contribute to development of more biofidelic models that can determine the extent and severity of injury in blast loadings. Such predictions are essential for designing better injury mitigation devices for soldiers and also for improving neurosurgical procedures among other applications. / Mechanical Engineering / Accompanied by one .pdf file.

Several efforts have been made in the past half century to characterize the behavior of brain tissue under different modes of loading and deformation rates; however each developed model has been associated with limitations. This dissertation aims at addressing the non-linear and rate dependent behavior of brain tissue specially in high strain rates (above 100 s-1) that represents the loading conditions occurring in blast induced neurotrauma (BINT) and development of a universal constitutive model for brain tissue that describes the tissue mechanical behavior from medium to high loading rates.. In order to evaluate the nature of nonlinearity of brain tissue, bovine brain samples (n=30) were tested under shear stress-relaxation loading with medium strain rate of 10 s-1 at strain levels ranging from 2% to 40% and the isochronous stress strain curves at 0,1 s and 10 s after the peak force formed. This approach enabled verification of the applicability of the quasilinear viscoelastic (QLV) theory to brain tissue and derivation of its elastic function based on the physics of the material rather than relying solely on curve fitting. The results confirmed that the QLV theory is an acceptable approximation for engineering shear strain levels below 40% that is beyond the level of axonal injury and the shape of the instantaneous elastic response was determined to be a 5th order odd polynomial with instantaneous linear shear modulus of 3.48±0.18 kPa. To investigate the rate dependent behavior of brain tissue at high strain rates, a novel experimental setup was developed and bovine brain samples (n=25) were tested at strain rates of 90, 120, 500, 600 and 800 s-1 and the resulting deformation and shear force were recorded. The stress-strain relationships showed significant rate dependency at high rates and was characterized using a QLV model with a 739 s-1 decay rate and validated with finite element analysis. The results showed the brain instantaneous elastic response can be modeled with a 3rd order odd polynomial and the instantaneous linear shear modulus was 19.2±1.1 kPa. A universal constitutive model was developed by combining the models developed for medium and high rate deformations and based on the QLV theory, in which the relaxation function has 5 time constants for 5 orders of magnitude in time (from 1 ms to 10 s) and therefore, is capable of predicting the brain tissue behavior in a wide range of deformation rates. Although the universal model presented in this study was developed based on only shear tests and the material parameters could not be found uniquely, by comparing the results of this study with previously available data in the literature under tension unique material parameters were determined for a 5 parameter generalized Rivlin elastic function (C10=3.208±0.602 kPa, C01=4.191±1.074 kPa, C11=79.898±18.974 kPa, C20=-37.093±7.273 kPa, C02=-37.712±5.678 kPa). The universal constitutive model for brain tissue presented in this dissertation is capable of characterizing the brain tissue behavior under large deformation in a wide range of strain rates and can be used in computational modeling of Traumatic Brain Injury (TBI) to predict injuries that result from falls and sports to automotive accidents and BINT. / Mechanical Engineering

Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation at high strain rates and then return to equilibrium following a brief negative pressure phase. This mechanical disruption of the tissue is known to cause oxidative stress and neuroinflammation in the brain, which can lead to neurodegeneration and consequently poor cognitive and behavioral outcomes. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure and there are currently no effective treatments. Thus, there is a need to investigate the acute molecular responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the acute molecular response, but how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the tissue-level biomechanics and the acute bTBI pathophysiology. In a rodent bTBI model, using adult rats, intracranial pressure was mapped throughout the brain during blast exposure where frequency contributions from skull flexure and wave dynamics were significantly altered between brain regions and were largely dependent on blast magnitude. These findings informed the subsequent spatial and temporal changes in neurometabolism. Amino acid molecular precursor concentrations decreased at four hours post-blast in the cortex and hippocampus regions. This motivates further investigation of amino acids as therapeutic targets aimed to reduce oxidative stress and prevent prolonged injury cascades. However, neurochemical changes were not consistent across blast magnitudes, which may be explained by the disparities in biomechanics at lower blast pressures. Lastly, we investigated the acute changes in metabolic regulators influencing excitotoxicity where it was found that astrocytes maintained normal clearance of excitatory and inhibitory neurotransmitters prior to astrocyte reactivity. Outcomes of this work provide improved understanding of blast mechanics and associated acute pathophysiology and inform future therapeutic and diagnostic approaches following bTBI. / Doctor of Philosophy / Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure wave rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation that can cause injury. This mechanical disruption of the tissue is known to trigger negative biological processes that lead to persistent cognitive and behavioral deficits. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure. There are currently no effective treatments that can help those afflicted, and biomarkers for injury diagnostics are limited. Thus, there is a great need to investigate the early biological responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the immediate responses, but also how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the brain biomechanics and the acute bTBI pathophysiology. Using a translational animal model, pressure inside the brain was measured with pressure sensors during blast exposure. Subsequent spatial and temporal changes in neurochemical concentrations were quantified. The results showed (1) significant disparities in the pressure dynamics inside the brain and it varied across brain regions, (2) neurochemical precursors may have therapeutic potential post-injury, and (3) biomechanical and neurochemical responses were dependent on blast severity. Outcomes of this work provide improved understanding of blast mechanics and associated pathophysiology and inform future therapeutic and diagnostic approaches to prevent prolonged injury cascades.